The proposed research will test the hypotheses that there are subtypes of histamine H2-receptors and that the H2-receptor-effector systems are subject to up and down regulation - depending upon the normal physiological tone of the system. H2-receptors will be characterized by their dissociation constants for strong and weak agonists. The apparent Kd values for agonism at H2-receptors in the guinea pig ileal myenteric plexus and guinea pig right atrium will be determined for the strong agonists histamine (atrium only) and dimaprit; and the weak agonists, nordimaprit, imidazoylpropylguanidine, and impromidine. Apparent Kd values will be determined by classical techniques employing the irreversibly acting H2-antagonists L-643,441 and BMY-25368. Computer assisted analysis of full dose response curves constructed before and after inactivation of a fraction of the active receptors will be carried out to estimate the dose-response parameters that will characterize the receptors as well as determine the strong-weak agonist pairs to be used in studies on up and down regulation of H2-receptors. Contractile responses will be measured in isolated ilei and chronotropic responses in isolated atria. Guinea pigs will be treated chronically with a competitive H2-antagonist, tiotidine, or an irreversible inhibitor of histamine synthesis, fluoromethylhistidine, to reduce tone at H2-receptors. Similarly, animals will be treated with an H2-agonist, dimaprit, to increase tone at H2-receptors. The effects of chronic treatment with pentagastrin will be studied to determine if H2-antagonist induced increases in circulating gastrin might in part be responsible for the anticipated results. Tissues will be obtained from treated animals and studied to determine if the treatments altered dose-response parameters in a manner consistent with changes in the concentration of active receptors as well as possible changes in the effector system. The results of these experiments will provide new information on GI H2-receptors and may be applicable to the therapeutic use of H2-antagonists.